Knock-out of the gene encoding sphingomyelin synthase SMase 1 in human monocytic leukemia cell line U cells was found to inhibit the phagocytosis of M. The phosphatase CD45 did remained at the receptor-pathogen contact site of nascent phagosomes.
In general, SM, one of the main components of membrane microdomains, is distributed uniformly on the outer leaflets of plasma membranes of cells, including human neutrophils Zachowski, ; Murate et al. Recently, our group found SM clusters on the inner leaflets of plasma membranes of human neutrophils Murate et al.
Sphingomyelinase, ceramidase, and sphingosine kinase, along with other related enzymes, are present in the cell cytosol Milhas et al. Therefore, cytosolic leaflet-associated SM would constitute a starting material for microdomains on phagosomal membranes, promoting phagolysosome maturation and the antigen presentation process.
KH searched the references, wrote the manuscript, and made a figure. TH searched the references and wrote the manuscript. KI organized the gathered references, made the concept, wrote the manuscript, and made a figure.
All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Abu Khweek, A. PLoS One e Ali, M. Cell Death Dis. Angstrom, J. The lactosylceramide binding specificity of Helicobacter pylori. Glycobiology 8, — Chiricozzi, E.
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Each micelle may contain thousands of lipid molecules. Polar lipids may also form a monolayer, a layer one molecule thick on the surface of the water.
The polar heads face into water, and the nonpolar tails stick up into the air. Bilayers are double layers of lipids arranged so that the hydrophobic tails are sandwiched between an inner surface and an outer surface consisting of hydrophilic heads. The hydrophilic heads are in contact with water on either side of the bilayer, whereas the tails, sequestered inside the bilayer, are prevented from having contact with the water. In the bilayer interior, the hydrophobic tails that is, the fatty acid portions of lipid molecules interact by means of dispersion forces.
The interactions are weakened by the presence of unsaturated fatty acids. As a result, the membrane components are free to mill about to some extent, and the membrane is described as fluid.
The lipids found in cell membranes can be categorized in various ways. Phospholipids are lipids containing phosphorus. Glycolipids are sugar-containing lipids. The latter are found exclusively on the outer surface of the cell membrane, acting as distinguishing surface markers for the cell and thus serving in cellular recognition and cell-to-cell communication.
Sphingolipids are phospholipids or glycolipids that contain the unsaturated amino alcohol sphingosine rather than glycerol. Phosphoglycerides also known as glycerophospholipids are the most abundant phospholipids in cell membranes.
There are two common types of phosphoglycerides. Phosphoglycerides containing ethanolamine as the amino alcohol are called phosphatidylethanolamines or cephalins. Cephalins are found in brain tissue and nerves and also have a role in blood clotting. Phosphoglycerides containing choline as the amino alcohol unit are called phosphatidylcholines or lecithins. Lecithins occur in all living organisms.
Like cephalins, they are important constituents of nerve and brain tissue. Egg yolks are especially rich in lecithins. Commercial-grade lecithins isolated from soybeans are widely used in foods as emulsifying agents. In these mice, single cell necrosis in the epithelia of crypts in the small and large intestines was observed as early as 24 h after inducing the knockout.
Thus, SPT is of particular importance in the proliferation and maintenance of mucosal epithelial cells. HSAN1A is an autosomal dominant axonal neuropathy. Initial symptoms are loss of pain, touch, heat, and cold sensation over the feet, followed by distal muscle wasting and weakness. It is largely unknown why this mutation causes defects in peripheral neurons not in central neurons. HSAN1-associated mutant SPT has a reduced preference for L-serine and an increased activity toward amino acid substrates specifically, alanine and glycine , which ultimately lead to the production of deoxy-type sphingosine bases.
Unexpectedly, very recent studies demonstrated that oral administration of L-serine reduces the formation of 1-deoxy sphingolipids in mice and humans with HSAN1. Peripheral neurons may be particularly sensitive to the HSAN1 mutation possibly because peripheral neurons have low levels of serine synthase activities, resulting in a high alanine-to-serine ratio. Unusual sphingolipid metabolites have also been detected in the blood plasma of diabetic patients.
Since catalytic activity is detectable when human GlcT-1 protein is expressed in E. However, little is known about how GlcT-1 activity is regulated and how its protein synthesis and degradation are controlled. Ceramide glucosylation occurs in the cytosolic side of the cis -Golgi membranes of mammals. GlcT-1 protein has never been isolated in pure form, since it is a hydrophobic protein and is a very minor component.
Since GlcT-1 is now expected to be a drug target for diabetes 35 , 36 and sphingolipidoses, 37 , 38 it is important to resolve its three-dimensional structure in order to develop new types of GlcT-1 inhibitors. Next, I discuss examples demonstrating the importance of GlcCer synthesis in vivo. Embryonic lethality of Ugcg knockout mice demonstrates that GlcCer synthesis is essential for development. It remains unclear, however, why eliminating the Ugcg gene enhances cell death selectively in ectoderm.
The use of different nestin-Cre transgene mouse lines could explain these disparate findings. To understand how GlcCer synthesis in the CNS contributes to post-mitotic neuronal survival and functional maintenance at the molecular level, we generated Purkinje neuron-specific knockout mice L7-GlcT-1KO mice using L7Cre transgenic mice.
Their doubly myelinated axons were enveloped by an additional concentric myelin sheath around the original sheath. Our data showed that axonal GlcCer-derived GSLs are essential for correct myelin sheath formation and maintenance.
Unlike the Purkinje neuron-specific knockout mice, oligodendrocyte-specific knockout mice, which were generated by using Cnp-Cre transgenic mice, do not show any abnormal myelin structures or functions.
In Drosophila , GlcCer synthesis is essential for embryo survival: Loss of GlcT-1 function causes excessive cell death in part due to caspase-dependent apoptosis. Although most organisms contain only one GlcCer synthase gene, C. This corroborates the initial proposal of De Smedt et al. Further studies are necessary to fully understand regulatory mechanisms mediated by GlcCer synthesis in oocyte meiosis.
Zhang et al. These recent studies examining the in vivo functions of GSLs suggest that GlcCer is not merely a precursor lipid needed for the synthesis of complex GSLs; rather, GlcCer itself exerts biological activities through unrecognized mechanisms.
It is also extremely important to address the key questions: Why is GlcCer formed in the cytosolic face of Golgi membranes and translocated into the luminal part of the membranes, and how does this occur? Recent pharmaceutical studies demonstrated that GlcCer synthesis is possibly involved in the pathogenesis of diabetes mellitus and atherosclerosis.
As we discussed above, small animal models such as C. The lipid raft hypothesis has had a wide impact not only on the field of membrane lipid biology but also more generally on the field of cell biology. This concept has lead to profound insight into membrane dynamics, especially lipid dynamics in living cells. Since there is enormous molecular diversity among membrane lipids, the existence of membrane lipid microdomains other than sphingolipid-rich domains is quite possible. Both of these lipids are possibly enriched in lipid rafts or membrane microdomains distinct from sphingolipid-rich domains.
Akiyama et al. It is interesting to note that ceramide generated from sphingomyelin is also a molecule important in stress responses. Recently it was observed that dynamic changes in the cholesterol-rich domain structure induced by heat stress or benzyl alcohol membrane fluidizer treatment is responsible for the activation of HSF1 and HSP In , Nagatsuka et al. Although the biological significance of this glycolipid puzzled us at that time, we decided to continue with the structural and functional analyses of the lipid.
Four years later, a similar lipid was isolated in detergent-insoluble membrane DIM fractions from human promyelocytic leukemia cells HL Thus, it was extremely difficult to purify and to obtain in a pure form.
Most unexpected was the finding that PtdGlc isolated from fetal rat brain has only one fatty acid combination: That is, the sn -1 and sn -2 chains are exclusively stearic acid C and arachidic acid C , respectively.
A single molecular species rarely occurs in natural phospholipids. Also, very few natural lipids have the C acyl chain as a major component. In addition, PtdGlc from rat brain contained a stereoisomer, 1- sn -phosphatidylglucoside. How this isomer is biosynthesized is unknown. These results suggest that the lack of tight intermolecular interactions exclude PtdGlc from other lipid domains on the plasma membrane. Immunoelectron microscopy with DIM21 using the SDS-digested freeze fracture replica labeling method demonstrated that PtdGlc forms distinct lipid domains exclusively on the outer, not inner, leaflet of the plasma membrane of HL60 cells and A cells, a human alveolar epithelial cell line.
Expression of PtdGlc is developmentally regulated in the rodent brain Fig. A high level of PtdGlc expression is observed in radial glia and astrocytes in early developing rat brains E At E In adults, neural stem cells Type B in the subventricular zone continuously express PtdGlc.
Developmental changes in PtdGlc expression in mouse cerebral cortex. In all images, cells labeled with DIM21 are green. Brain lipid-binding protein BLBP is a radial glia marker. The biological roles of PtdGlc are poorly understood. Since PtdGlc is enriched in astrocyte lineage cells in the developing mouse CNS, they may be potentially involved in astrogliogenesis in mouse cerebral cortex.
This notion is supported by the finding that addition of DIM21 to neural progenitor cells prepared from fetal mouse telencephalon causes the recruitment of EGF receptors into lipid rafts, leading to the activation of EGF receptors.
PtdGlc has been found also in epithelial cells from various human organs. In neutrophils, DIM21 treatment induces Fas clustering, leading to Fas-dependent apoptotic cell death, 80 Moreover, these Fas clusters colocalize with PtdGlc to form large rafts.
It is surprising to have identified a novel glycolipid molecule, PtdGlc, in mammalian tissues, even in this century. All glucose-modified lipids should have very important biological functions, since evolutionarily glucose is a very old sugar and most organisms use it for their survival.
Thus, it is quite understandable that GlcCer, sphingolipids, and sphingoglycolipids are heavily involved in energy metabolism for our whole body. Further studies are necessary to understand the molecular mechanisms by which energy homeostasis is tightly regulated.
Model animals such as Drosophila and C. In contrast to GlcCer, the hydrophobic acyl-chains of PtdGlc are easily hydrolyzed by phospholipases. Rapid progress of technologies in mass spectrometry enables us to discover the unique lipid molecule in the developing CNS. We believe that this lyso-lipid plays important roles in a variety of biological processes in both nervous systems and non-nervous systems. To understand the precise roles of PtdGlc and its metabolites, it is crucial to identify the enzyme involved in the glucosylation of PtdGlc and the gene that encodes it.
Exogenous addition of lyso-phosphatidylglucoside induces growth cone collapse of rat DRG neurons. DRG neurons were isolated from an E Actin filaments were visualized with rhodamine-labeled phalloidin M. Yamazaki et al.
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